4-hydroxy-2,n-dimethyl-2h-1,2-benzothiazine-3-carboxanilide1,1-dioxide and process therefor

ABSTRACT

A compound of the formula is disclosed:   This compound is prepared as follows:   It is useful as an anti-inflammatory agent.

United States Patent m1 Zinnes et al.

[ 1 Jan. 30, 1973 [54] 4-HYDROXY-2,N-DlMETHYL-2H-l,2-

BENZOTHlAZlNE-3- CARBOXANILIDEl,l-DIOXIDE AND PROCESS THEREFOR [75]Inventors: Harold Zinnes, White Meadow Lake, Rockaway; Neil A. Lindo,.Chatham; John Shavel, Jr., Mendham, all of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[22] Filed: Sept. 27, 1971 [21] Appl. No.: 184,193-

[52] US. Cl. ..260/243 R, 424/246 [51] Int. Cl. ..C07d 93/02 [58] Fieldof Search ..260/243 R [56] References Cited UNITED STATES PATENTS3,646,020 2/1972 Zinnes et al. ..260/243 Primary ExaminerJ0hn M. FordAttorney-Albert H. Graddis et al.

This compound is prepared as follows:

It is usefiil as an anti-inflammatory agent.

3 Claims, No Drawings l CONCoHs NCH:

The above compound is useful as an anti-inflammatory agent. Whenadministered orally or intraperitoneally to mammals, such as rats, indoses of 100 to 250 mg/kg, it reduces the swelling of the paw induced byinjection into the foot pads of an irritant such as carrageenin.

Accordingly, the compound of this invention is indicated in conditionssuch as arthritis in a mammal such as cats, dogs, monkeys, and the like.A dosage regimen of 100 to 250 mg/kg orally or by injection severaltimes a day is recommended. This dosage regimen can be varied inaccordance with age, weight and severity of the condition being treated.

in order to use this compound, it is formulated into dosage formscommonly used in oral or in parenteral administration. These include,e.g., tablets, capsules, suspensions, solutions for injection, and thelike. These formulations are prepared by mixing the active ingredientwith pharmaceutical excipients such as lactose, dicalcium phosphate andsterile water and compounded by methods well known to the pharmacistsart to give final forms containing 100 to 250 mg per dosage unit.

According to the present invention, the above compound is prepared inaccordance with the following reaction scheme:

CONHCeHi v CONCo s 1. Base NCH; I NCH;

2. Methylating Agent Referring now to the above reaction scheme, acompound of Formula I is converted to the anion by the use of a base andtreating the resulting anion with a methylating agent, such as dimethylsulphate.

The starting Compound I is prepared by treating 2- methyl-ZH-l,2-benzothiazine-4-(3H )-one l,l-dioxide with a base and treating theanion thus obtained with phenylisocyanate.

Among the bases which can be used for the conversion of the abovestarting materials to their respective anions are alkali metal hydridessuch as sodium hydride and Grignard reagents such as isopropylmagnesiumhalide.

The starting compound for 2-methyl-2H-l ,2- benzothiazine-4-(3H)-onel,l-dioxide is prepared in accordance with the teachings of Zinnes, etal, Journal ofOrganic Chemistry 3 l 162 (1966).

The following examples are included in order further to illustrate theinvention.

EXAMPLE 1 4-l-lydroxy2-M ethyl-3Phenylcarbamyl-ZH-l ,2- Benzothiazine l,1 Dioxide A. Sodium Hydride as the Base A solution of 31.7 g (0.15 mol)of 2-methyl-2l-l-1,2- benzothiazin-4(3H)-onel,l-dioxide in 300 ml oftetrahydrofuran was added dropwise with stirring over a period of 45minutes to a slurry of 0. l 7 mol of sodium hydride in ml oftetrahydrofuran, the temperature being maintained at 0 to 5C. When gasevolution had ceased, a solution of 40 g (0.34 mol) of phenylisocyanatein 100 ml of tetrahydrofuran was added at such a rate that thetemperature remained at 5C. It was then allowed to stand at roomtemperature for one hour and the solvent was removed in vacuo at roomtemperature. The residue was poured into 500 ml of ice water, themixture was filtered, and the filtrate was washed with ether. Theaqueous solution was acidified with hydrochloric acid and the resultingprecipitate was collected. Recrystallization from ethyl acetate gave29.6 g ofproduct, m.p. 217 to 218.5C dec.

Anal. for C l-l N 0 S:

Calcd: C 58.18 H 4.27 N 8.48 S 9.71

Found: C 58.38 H 4.24 N 8.62 S 9.80 B. Grignard Reagent as the Base TheGrignard reagent prepared from 0.8 g of magnesium and 2.6 g of isopropylchloride in 25 ml of ether was diluted with 25 ml of tetrahydrofuran anda solution of 6.3 g (0.03 mol) of 2-methyl-2H-1,2-benzothiazin-4(3H)-one l,l-dioxide in 25 ml of tetrahydrofuran wasadded. The mixture was stirred for 15 minutes, a solution of 3.9 g(0.033 mol) of phenylisocyanate was added, and it was refluxed for 3hours. Most of the solvent was evaporated in vacuo, the residue waspoured into ice water containing excess hydrochloric acid, and theresulting mixture was extracted with ether. The ether solution wasextracted with 1N aqueous sodium hydroxide and the aqueous layer waswashedwith ether. it was reacidified and extracted withdichloromethane'. Evaporation of the dichloromethane gave a residuewhich was triturated with ether to give 2.2 g of crystalline-product,m.p. 207"-2l2C dec. Recrystallization from methanol raised the m.p. to217 -2l8.SC dec.

EXAMPLE 2 NCH:

4-Hydroxy-2,NeDimethyl-2l l-1,2-Benzothiazine-3- Carboxanilide 1,1-Dioxide To a slurry of 0.05 mol (2.1 g ofa 57 percent mineral oildispersion) of sodium hydride in 50 ml of tetrahydr'ofuran was added asolution of 6.6 g (0.02 mol) of4-hydroxy-2-methyl-2H-l,2-benzothiazine-3- carboxanilide 1,1-dioxide in150 ml of tetrahydrofuran, the temperature being maintained at to 10Cduring the, addition. A solution of 2.6 g (0.021 mol) of dimethylsulfate in 10 ml of tetrahydrofuran was added, the reaction mixture wasallowed to slowly warm to room temperature, and then refluxed for twohours. Most of the solvent was removed and the residue was treated withice water. The mixture was filtered and the filtrate was acidified withdilute hydrochloric acid. The resulting crude precipitate wasrecrystallized from methanol to give 3.9 g of crystalline product, m.p.175-l78C.

Anal. for C,,H, N,O D:

Calcd: C 59.29 H 4.68 N 8.13 S 9.31

Found: C 59.01 H 4.65 N 8.04 S 9.51

We claim:

l. A compound ofthe formula:

(3H3 C ON CuHs 2. A process for the production of a compound of theformula:

N-CONHCcHa /NCH:

which comprises treating:

a. Z-methyl-ZH-l ,2-benzothiazine-4(3H)-one dioxide with sodium hydride,and b. treating the anion obtained in (a) with phenylisowhich comprisestreating:

a. 2-methyl-2H-1,2-benzothiazine-4(3l-l)-one dioxide with an alkylmagnesium halide, and b. treating the anion obtained from (a) withphenyl isocyanate.

1. A compound of the formula:
 2. A process for the production of acompound of the formula: